1. Cancer Biology
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Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

  1. Delphine Fessart  Is a corresponding author
  2. Charlotte Domblides
  3. Tony Avril
  4. Leif A Eriksson
  5. Hugues Begueret
  6. Raphael Pineau
  7. Camille Malrieux
  8. Nathalie Dugot-Senant
  9. Carlo Lucchesi
  10. Eric Chevet
  11. Frederic Delom
  1. Université de Bordeaux, France
  2. University of Rennes 1, France
  3. University of Gothenburg, Sweden
  4. Hôpital Haut-Lévêque, France
  5. Bergonié Cancer Institute, France
Research Article
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Cite this article as: eLife 2016;5:e13887 doi: 10.7554/eLife.13887

Abstract

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.

Article and author information

Author details

  1. Delphine Fessart

    Université de Bordeaux, Bordeaux, France
    For correspondence
    delphine.fessart@yahoo.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Charlotte Domblides

    Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Tony Avril

    Oncogenesis, Stress, Signaling, University of Rennes 1, Rennes, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Leif A Eriksson

    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Hugues Begueret

    Hôpital Haut-Lévêque, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Raphael Pineau

    Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Camille Malrieux

    Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Nathalie Dugot-Senant

    Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Carlo Lucchesi

    Bergonié Cancer Institute, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Eric Chevet

    Oncogenesis, Stress, Signaling, University of Rennes 1, Rennes, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Frederic Delom

    Université de Bordeaux, Bordeaux, France
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal procedures met the European Community Directive guidelines (Agreement B33-522-2/ Number DIR 1322) and were approved by the ethical committee from Bordeaux University.

Human subjects: Samples of human lung cancer tissues were obtained from the Haut-Leveque University Hospital (Bordeaux, France) and reviewed by expert pathologist in the field (H. Begueret). These procedures were approved by the Institutional Review Board at Haut-Leveque (NFS96900 Certification).

Reviewing Editor

  1. Johanna Ivaska, University of Turku, Finland

Publication history

  1. Received: December 17, 2015
  2. Accepted: May 28, 2016
  3. Accepted Manuscript published: May 30, 2016 (version 1)
  4. Version of Record published: July 11, 2016 (version 2)

Copyright

© 2016, Fessart et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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